title: Hunk is required for HER2/neu-induced  mammary tumorigenesis.
abstract: Understanding the molecular pathways that contribute to the aggressive behavior of human cancers is a critical research priority. The SNF1/AMPK-related protein kinase Hunk is overexpressed in aggressive subsets of human breast, ovarian, and colon cancers. Analysis of Hunk(–/–) mice revealed that this kinase is required for metastasis of c-myc–induced mammary tumors but not c-myc–induced primary tumor formation. Similar to c-myc, amplification of the proto-oncogene HER2/neu occurs in 10%–30% of breast cancers and is associated with aggressive tumor behavior. By crossing Hunk(–/–) mice with transgenic mouse models for HER2/neu-induced mammary tumorigenesis, we report that Hunk is required for primary tumor formation induced by HER2/neu. Knockdown and reconstitution experiments in mouse and human breast cancer cell lines demonstrated that Hunk is required for maintenance of the tumorigenic phenotype in HER2/neu-transformed cells. This requirement is kinase dependent and resulted from the ability of Hunk to suppress apoptosis in association with downregulation of the tumor suppressor p27(kip1). Additionally, we find that Hunk is rapidly upregulated following HER2/neu activation in vivo and in vitro. These findings provide what we believe is the first evidence for a role for Hunk in primary tumorigenesis and cell survival and identify this kinase as an essential effector of the HER2/neu oncogenic pathway.
authors.affiliation: Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Yeh
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Yang
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Jung
authors.forename: Heather P
authors.initials: HP
authors.lastname: Gardner
authors.forename: Robert D
authors.initials: RD
authors.lastname: Cardiff
authors.forename: Lewis A
authors.initials: LA
authors.lastname: Chodosh
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D009368:Neoplasm Transplantation; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
chemical_list: D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; C000715470:MAS1 protein, human; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse; C549065:HUNK protein, human; C417729:Hunk protein, mouse